Abstract Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). It is the most common autoimmune disease affecting the CNS. Although much attention has focused on the immunological mechanisms in MS, new evidence suggests that oxidative stress also induces MS neuropathology. Myeloperoxidase (MPO) is a powerful peroxidative enzyme that has long been considered a therapeutic target in MS. To inhibit MPO toxic oxidant production we designed N-acetyl lysyltyrosylcysteine amide (KYC) and showed that KYC effectively reduced neurological disease severity scores in EAE mice by sealing the blood brain barrier and reducing myeloid cell recruitment (J Neurochem. 2015; PMID: 26560636). Our current research suggests KYC reduces MPO-dependent activation of neutrophils, and possibly other myeloid cells whose function and phenotype are linked to MPO. KYC does not ?kill? MPO activity rather it depletes MPO, of its high-energy iron-bound peroxyl radicals thereby reducing oxidative damage to the CNS. When KYC is present, it efficiently ?shuttles? MPO radicals into the glutathione pathway, essentially turning MPO into a quasi-catalase that effectively reduces oxidative stress in MS. In our published murine studies KYC was administered via intraperitoneal (i.p.) injection, which is not an acceptable delivery route in humans. Additional studies are required to determine if KYC administration by subcutaneous (s.c.) or intranasal (i.n.) are as effective as i.p. since both s.c. and i.n. are routes of therapeutic delivery routinely used in humans with MS. After optimizing KYC routes of delivery, we will do head-to-head comparisons of KYC to dimethyl fumarate (DMF). Accordingly, the goal of our SBIR Phase I studies is ? KYC administration via s.c. or i.n. is equal or superior to DMF in ameliorating EAE disease severity. Aim 1 will define clinically relevant KYC dosing regimens. Aim 2 will compare KYC therapeutic dosing to DMF therapeutic dosing in established EAE models. Milestones: Aim 1 = KYC (s.c. or i.n.) decreases EAE severity equal to or better than i.p. KYC. Aim 2 = KYC reduces EAE disease severity equal or superior to DMF. If proof-of-concept is established in these SBIR Phase I studies, ReNeuroGen, LLC will design and develop a realistic and compelling Phase II plan, raise capital from angel investors and apply for Phase II SBIR\STTR funding that will be used for contracting GLP labs to perform the preclinical safety, pharmacokinetic, pharmacodynamic and toxicology studies to generate the data that are required for filing an IND with the FDA.